2-aminoquinolinecarboxamides: neurokinin receptor ligands

ABSTRACT

Disclosed are compounds of the formula:                  
 
or pharmaceutically acceptable salts or pharmaceutically acceptable solvates thereof,
 
wherein R 1 , R 2 , R 3 , X, Q 1  and Q 2  are defined herein,
         which compounds are ligands for neurokinin receptors, in particular NK-3 receptors, and are therefor useful in the treatment of a wide range of diseases or disorders including, but not limited to depression, anxiety, psychosis, obesity, pain, Parkinson&#39;s disease, Alzheimer&#39;s disease, neurodegenerative diseases, movement disorders, respiratory diseases, inflammatory diseases, neuropathy, immune disorders, migraine, biliary disfunction, and dermatitis.

This is a continuation of prior application Ser. No. 10/115,409, filedApr. 3, 2002 now U.S. Pat. No. 6,894,044.

This application claims priority from provisional application No.60/131,025 filed Apr. 26, 1999 which is incorporated herein by referencein its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to 2-aminoquinolinecarboxamides, pharmaceuticalcompositions comprising them, and the use of such compounds in thetreatment of certain central nervous system and peripheral diseases. Thecompounds of this invention are also useful as probes for thelocalization of cell surface receptors.

2. Description of the Related Art

The tachykinins represent a family of structurally related peptidesoriginally isolated based upon their smooth muscle contractile andsialogogic activity. These mammalian peptides include substance P (SP),neurokinin A (NKA) and neurokinin β (NKB). Tachykinins are synthesizedin the central nervous system (CNS), as well as in peripheral tissues,where they exert a variety of biological activities. Substance P can beproduced from three different mRNAs (α-, β- and γ-preprotachykininmRNAs) that arise from a single gene as a result of alternative RNAsplicing, whereas NKA can be generated from either the β- or theγ-preprotachykinin mRNA through posttranslationally processed precursorpolypeptides. These precursors can also be differentially processed sothat amino terminally extended forms of NKA (known as neuropeptide K andneuropeptide γ) are produced. NKB is produced from a separate mRNAarising from a second gene known as preprotachykinin B.

Three receptors for the tachykinin peptides have been molecularycharacterized and are referred to as neurokinin-1 (NK-1), neurokinin-2(NK-2) and neurokinin-3 (NK-3) receptors. The NK-1 receptor has anatural agonist potency profile of SP>NKA>NKB. The NK-2 receptor agonistpotency profile is NKA>NKB>SP, and the NK-3 receptor agonist potencyprofile is NKB>NKA>SP. These receptors mediate the variety oftachykinin-stimulated biological effects that generally include 1)modulation of smooth muscle contractile activity, 2) transmission of(generally) excitatory neuronal signals in the CNS and periphery (e.g.pain signals), 3) modulation of immune and inflammatory responses, 4)induction of hypotensive effects via dilation of the peripheralvasculature, and 5) stimulation of endocrine and exocrine glandsecretions. These receptors transduce intracellular signals via theactivation of pertussis toxin-insensitive (G_(aq/11)) G proteins,resulting in the generation of the intracellular second messengersinositol 1,4,5-trisphosyphate and diacylglycerol. NK-1 receptors areexpressed in a wide variety of peripheral tissues and in the CNS. NK-2receptors are expressed primarily in the periphery, while NK-3 receptorsare primarily (but not exclusively) expressed in the CNS. Recent workconfirms the presence of NK-3 receptor binding sites in the human brain.

Studies measuring the localization of NKB and NK-3 receptor mRNAs andproteins, along with studies performed using peptide agonists andnon-peptide NK-3 receptor antagonists, provide a rationale for usingNK-3 receptor antagonists in treating a variety of disorders in both theCNS and the periphery. In the CNS, activation of NK-3 receptors has beenshown to modulate dopamine and serotonin release, indicating therapeuticutility in the treatment of a variety of disorders including anxiety,depression, schizophrenia and obesity. Further, studies in primate braindetect the presence of NK-3 mRNA in a variety of regions relevant tothese disorders. With regard to obesity, it has also been shown thatNK-3 receptors are located on MCH-containing neurons in the rat lateralhypothalamus and zona incerta. In the periphery, administration of NKBinto the airways is known to induce mucus secretion andbronchoconstriction, indicating therapeutic utility for NK-3 receptorantagonists in the treatment of patients suffering from airway diseasessuch as asthma and chronic obstructive pulmonary disease (COPD).Localization of NK-3 receptors in the gastrointestinal (GI) tract andthe bladder indicates therapeutic utility for NK-3 receptor antagonistsin the treatment of GI and bladder disorders including inflammatorybowel disease and urinary incontinence.

Both peptide and nonpeptide antagonists have been developed for each ofthe tachykinin receptors. The first generation of peptide antagonistsfor the tachykinin receptors had problems with low potency, partialagonism, poor metabolic stability and toxicity, whereas the currentgeneration of non-peptide antagonists display more drug-like properties.Unfortunately, previous non-peptide NK-3 receptor antagonists sufferfrom a number of problems such as species selectivity (which limits thepotential to evaluate these compounds in many appropriate diseasemodels). New non-peptide NK-3 receptor antagonists are therefore beingsought, both as therapeutic agents and as tools to further investigatethe anatomical and ultrastructural distribution of NK-3 receptors, aswell as the physiologic and pathophysiologic consequences of NK-3receptor activation.

SUMMARY OF THE INVENTION

This invention relates to 2-aminoquinolinecarboxamides represented bystructure Formula I:

or pharmaceutically acceptable salts or pharmaceutically acceptablesolvates thereof, wherein in R₁, R₂, R₃, X, Q₁ and Q₂ are hereinafterdefined.

The invention also relates to pharmaceutical compositions comprisingsuch compounds and the use of such compounds and compositions in thetreatment of certain central nervous system and peripheral diseases ordisorders.

The compounds of this invention are ligands for neurokinin receptors, inparticular NK-3 receptors, and are useful in the treatment of a widerange of diseases or disorders including, but not limited to depression,anxiety, psychosis, obesity, pain, Parkinson's disease, Alzheimer'sdisease, neurodegenerative diseases, movement disorders, respiratorydiseases, inflammatory diseases, neuropathy, immune disorders, migraine,biliary disfunction, and dermatitis.

The invention provides novel 2-aminoquinolinecarboxamides that bindselectively to neurokinin receptors, in particular NK-3 receptors. Thesecompounds are therefore of use in the treatment of a broad array ofdiseases which are characterized by modulation of the neurokininreceptors, in particular NK-3 receptors.

In a separate aspect, the invention provides methods of using compoundsof this invention as positive controls in assays for receptor activityand using appropriately labeled compounds of the invention as probes forthe localization of receptors, particularly neurokinin-3 receptors, intissue sections.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to 2-aminoquinolinecarboxamides, pharmaceuticalcompositions comprising them, and the use of such compounds in thetreatment of certain central nervous system and peripheral diseases ordisorders.

Accordingly, a broad embodiment of the invention is directed tocompounds of Formula I:

or pharmaceutically acceptable salts or pharmaceutically acceptablesolvates thereof, wherein:

-   R₁ is:    -   hydrogen, halogen, hydroxy, C₁₋₆ alkyl, —O(C₁₋₆ alkyl), —NO₂,        —CN, —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl) (C₁₋₆        alkyl), amino, —NH (C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl),        —N(C₁₋₆ alkyl)CO(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —N(C₁₋₆        alkyl)CO₂(C₁₋₆ alkyl), —NHSO₂(C₁₋₆ alkyl), —N(C₁₋₆        alkyl)SO₂(C₁₋₆ alkyl), —SO₂NHCO(C₁₋₆ alkyl), —CONHSO₂(C₁₋₆        alkyl), —CON(C₁₋₆ alkyl)(C₁₋₆ alkyl), —CO₂(C₁₋₆ alkyl), —S(C₁₋₆        alkyl), —SO(C₁₋₆ alkyl), or —SO₂(C₁₋₆ alkyl),    -   where each C₁₋₆ alkyl is a straight, branched or cyclic alkyl        group optionally containing one or two double or triple bonds        and optionally substituted with one or more of hydroxy, oxo,        halogen, amino, or C₁₋₃ alkoxy;-   R₂ and R₃ are independently selected from the groups consisting of:    -   hydrogen, halogen, hydroxy, C₁₋₈ alkyl, —O(C₁₋₈ alkyl), —NO₂,        —CN, —SO₂NH₂, —SO₂NH(C₁₋₈ alkyl), —SO₂N(C₁₋₈ alkyl) (C₁₋₈        alkyl), amino, —NH(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl),        —N(C₁₋₈ alkyl)CO(C₁₋₈ alkyl), —NHCO₂(C₁₋₆ alkyl), —N(C₁₋₈        alkyl)CO₂(C₁₋₈ alkyl), —NHSO₂(C₁₋₈ alkyl), —N(C₁₋₆        alkyl)SO₂(C₁₋₈ alkyl), —SO₂NHCO(C₁₋₈ alkyl), —CONHSO₂(C₁₋₈        alkyl), —CON(C₁₋₈ alkyl)(C₁₋₈ alkyl), —CO₂(C₁₋₈ alkyl), —S(C₁₋₈        alkyl), —SO(C₁₋₈ alkyl), —SO₂(C₁₋₈ alkyl), and Ar,    -   wherein Ar is phenyl, naphthyl, thienyl, benzothienyl, pyridyl,        quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl,        furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isothiazolyl,        benzisothiazolyl, triazolyl, tetrazolyl, pyrazolyl, or        benzopyrazolyl, each of which is optionally substituted with one        or more of:        -   halogen, hydroxy, C₁₋₆ alkyl, —O(C₁₋₆ alkyl), —NO₂, —CN,            —SO₂NH₂, —SO₂NH(C₁₋₆ alkyl), —SO₂N(C₁₋₆ alkyl)(C₁₋₆ alkyl)            amino, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)(C₁₋₆ alkyl), —N(C₁₋₆            alkyl)CO(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —N(C₁₋₆            alkyl)CO₂(C₁₋₆ alkyl), —NHSO₂(C₁₋₆ alkyl), —N(C₁₋₆            alkyl)SO₂(C₁₋₆ alkyl), —SO₂NHCO(C₁₋₆ alkyl), —CONHSO₂(C₁₋₆            alkyl), —CON(C₁₋₆ alkyl)(C₁₋₆ alkyl), —CO₂(C₁₋₆ alkyl),            —S(C₁₋₆ alkyl), —SO(C₁₋₆ alkyl), or —SO₂(C₁₋₆ alkyl),    -   where    -   each C₁₋₆ alkyl is as defined above for R₁; and    -   each C₁₋₈ alkyl is a straight, branched or cyclic alkyl group        optionally containing one or two double or triple bonds and        optionally substituted with one or more of:        -   (i) hydroxy,        -   (ii) oxo,        -   (iii) halogen,        -   (iv) Ar, wherein Ar is as defined above,        -   (v) —NR₄R₅, wherein R₄ and R₅ are independently selected            from:            -   (A) hydrogen;            -   (B) C₁₋₆ alkyl, wherein C₁₋₆ alkyl is as defined above                for R₁;            -   (C) Ar, where in Ar is as defined above;            -   (D) C₁₋₆ alkyl-Ar, wherein Ar is as defined above and Ar                is attached to any position of the C₁₋₆ alkyl group at                any position of Ar;        -   or R₄ and R₅ together form a 4- to 8-membered monocyclic or            bicyclic nitrogen-containing ring which may contain:            -   (a) one or two double bonds;            -   (b) one or two oxo;            -   (c) one or two of O, S or N—R₆ wherein R₆ is hydrogen,                C₁₋₆ alkyl, C₁₋₆ alkyl-Ar, wherein C₁₋₆ alkyl and Ar are                defined as above and Ar is attached to to any position                of the C₁₋₆ alkyl group at any position of Ar; or            -   (d) one or two of R₁ where R₁ is as defined above;        -   (vi) —OR₄, wherein R₄ is as defined above;        -   (vii) —CONR₄R₅, wherein R₄ and R₅ are as defined above;        -   (viii) —SO₂NR₄R₅, wherein R₄ and R₅ are as defined above;        -   (x) —NR₄COR₅, wherein R₄ and R₅ are as defined above;-   X is O, S or N—CN;-   Q₁ and Q₂ are independently selected from formulas II and III:

-   -   wherein    -   R₇ is hydrogen or C₁₋₈ alkyl;    -   C₁₋₈ alkyl is as defined above;    -   R₈ and R₉ are independently selected from:        -   (i) hydrogen;        -   (ii) Ar′, wherein Ar′ is phenyl, naphthyl, thienyl,            benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl,            imidazolyl, benzoimidazolyl, furanyl, benzofuranyl,            thiazolyl, benzothiazolyl, isothiazolyl, benzisothiazolyl,            triazolyl, tetrazolyl, pyrazolyl, or benzopyrazolyl, each of            which is unsubstituted or substituted with one or more of:            -   halogen, hydroxy, C₁₋₈ alkyl, —O(C₁₋₈ alkyl), —NO₂, —CN,                —SO₂NH₂, —SO₂NH (C₁₋₈ alkyl), —SO₂N(C₁₋₈ alkyl)(C₁₋₈                alkyl), amino, —NH(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)(C₁₋₈                alkyl), —N(C₁₋₈ alkyl)CO(C₁₋₈ alkyl), —NHCO₂(C₁₋₆                alkyl), —N(C₁₋₈ alkyl)CO₂(C₁₋₈ alkyl), —NHSO₂(C₁₋₈                alkyl), —N(C₁₋₆ alkyl)SO₂(C₁₋₈ alkyl), —SO₂NHCO(C₁₋₈                alkyl), —CONHSO₂(C₁₋₈ alkyl), —CON(C₁₋₈ alkyl)(C₁₋₈                alkyl), —CO₂(C₁₋₈ alkyl), —S(C₁₋₈ alkyl) —SO(C₁₋₈                alkyl), or —SO₂(C₁₋₈ alkyl), wherein C₁₋₈ alkyl and C₁₋₆                alkyl are as defined above;        -   (iii) C₁₋₈ alkyl, wherein said C₁₋₈ alkyl is as defined            above,        -   (iv) —COR₄, wherein R₄ is as defined above,        -   (v) —CONR₄R₅, wherein R₄ and R₅ are as defined above,        -   (vi) —SO₂NR₄R₅, wherein R₄ and R₅ are as defined above.    -   or R₈ and R₉ together form a 4- to 8-membered monocyclic or        bicyclic ring which may contain:        -   (a) one or two double bonds;        -   (b) one or two oxo;        -   (c) one or two O, S or N—R₁₀ wherein R₁₀ is hydrogen, C₁₋₈            alkyl, C₁₋₈ alkyl-Ar′, wherein C₁₋₈ alkyl and Ar′ are            defined as above and Ar′ may be attached to C₁₋₈ alkyl at            any position; or        -   (d) one or two R₁ groups.

Preferred compounds of the invention include those of Formula I where Q₁is a group of the formula I-g:

where

-   Ar′ is phenyl optionally substituted with one or more of halogen,    hydroxy, C₁₋₈ alkyl, —O(C₁₋₈ alkyl), —NO₂, —CN, amino, —NH(C₁₋₈    alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)CO(C₁₋₈ alkyl),    —NHCO₂(C₁₋₆ alkyl), —N(C₁₋₈ alkyl)CO₂(C₁₋₈ alkyl), —CON(C₁₋₈    alkyl)(C₁₋₈ alkyl), —CO₂(C₁₋₈ alkyl), wherein C₁₋₈ alkyl and C₁₋₆    alkyl are as defined above; and-   R_(q) is straight or branched chain alkyl having from 1–6 carbon    atoms.

More preferred compounds of Formula I where Q₁ is a group of formula I-ginclude those where X is oxygen. Particularly preferred are suchcompounds where R₁ and R₂ are both hydrogen.

Formula I-g encompasses the following groups:

where Ar′ and R_(q) carry the same definitions as given above forformula I-g.

The invention encompasses compounds having Q₁ groups represented byeither of formulas I-h or I-k.

Other preferred compounds of Formula I include those of Formula I-A:

where R_(q) is straight or branched chain alkyl having from 1–6 carbonatoms; and

-   Q₂ is as defined above for Formula I.

Particularly preferred compounds of Formula I-A are those where R_(q) isethyl; Q₂ represents formula I or formula II where R₇ is defined asabove and R₈ and R₉ are independently selected from:

-   -   hydrogen;    -   C₁₋₈ alkyl, wherein said C₁₋₈ alkyl is as defined above; or    -   R₈ and R₉ together form a 4- to 8-membered monocyclic or        bicyclic ring which may contain:        -   (a) one or two double bonds;        -   (b) one or two oxo;        -   (c) one or two O, S or N—R₁₀ wherein R₁₀ is hydrogen, C₁₋₈            alkyl, C₁₋₈ alkyl-Ar′, wherein C₁₋₈ alkyl and Ar′ are            defined as above and Ar′ may be attached to C₁₋₈ alkyl at            any position; or        -   (d) one or two R₁ groups.

Still other preferred compounds of Formula I include those of FormulaI-B:

Wherein:

-   R_(q) is straight or branched chain alkyl having from 1-6 carbon    atoms;-   R₃ is C₁₋₆ alkyl or C₁₋₆ alkoxy; and-   Q₂ is as defined above for Formula I.

Particularly preferred compounds of Formula I-B are those where R_(q) isethyl; and

-   Q₂ is a group of the formula:

-   -   wherein R₈ and R₉ together form a 4- to 8-membered monocyclic or        bicyclic ring which may contain:    -   (a) one or two double bonds;    -   (b) one or two oxo;    -   (c) one or two O, S or N—R₁₀ wherein R₁₀ is hydrogen, C₁₋₈        alkyl.

The compounds of Formula I may contain one or more asymmetric centers,so that the compounds can exist in different stereoisomeric forms. Allstereoisomeric forms (e.g., optical isomers) and mixtures thereof areencompassed by the invention. The compounds containing asymmetriccenters can be, for example, racemates or optically active forms. Inthese situations, the single enantiomers, i.e., optically active forms,can be obtained by asymmetric synthesis or by resolution of theracemates. Resolution of the racemates can be accomplished, for example,by conventional methods such as crystallization in the presence of aresolving agent, or chromatography, using, for example a chiral HPLCcolumn.

In addition compounds of Formula I with carbon-carbon double bonds mayoccur in the Z- and/or E-forms. All such isomeric forms of suchcompounds are encompassed within the invention. Further, such compoundsmay be prepared in either pure E or pure Z forms using methods known tothose skilled in the art.

When any variable (e.g. C₁₋₆ alkyl, C₁₋₈ alkyl, R₁–R₉, Q₁ or Q₂) occursmore than one time in Formula I, its definition on each occurrence isindependent of its definition at every other occurrence.

As used herein, the term “alkyl” includes those alkyl groups of adesigned number of carbon atoms. Examples of “alkyd ” include methyl,ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl,hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, norbornyl, and the like. When reference is madeherein to C₁₋₆ alkyl or C₁₋₈ alkyl which it may contain one or twodouble or triple bond it is understood that at least two carbons arepresent in the alkyl for one double or triple bond, and at least fourcarbons for two double or triple bonds. “Alkoxy” represents an alkylgroup of indicated number of carbon atoms attached through an oxygenbridge, such as methoxy, ethoxy, propoxy and isopropoxy.

By “halogens” herein is meant fluorine, chlorine, bromine, and iodine.Preferred halogens are fluorine and chlorine. Particularly preferred isfluorine.

As used herein, the terms “patient” and “patients” refer to humans aswell as other mammals including pets such as dogs and cats and livestocksuch as cattle and sheep.

By C₁₋₆ alkyl-Ar as used herein is meant an aryl (Ar) group substitutedon an alkyl group which is in turn connected to the parent structure.Examples of such groups are benzyl, phenethyl, 1-naphthylmethyl,2-pyridylmethyl, and 3-pyimidin-2-ylpropyl.

This invention also includes methods for using compounds of Formula I totreat diseases or disorders in patients in which mediation by NK-3receptors is of importance.

The compounds of this invention are ligands for neurokinin receptors, inparticular NK-3 receptors, and are useful in the treatment of a widerange of diseases or disorders of the central nervous system (CNS) andperiphery in mammals in which modulation of NK-3 receptors is ofimportance. These include depression, anxiety, panic disorder, obsessivecompulsive disorder, psychosis and schizophrenia, neurodegenerativedisorders such as dementia, Alzheimer's diseases, Parkinson's disease,Huntington's disease, stress related somatic disorders, reflexsympathetic dystrophy, dysthmic disorders, obesity, eating disorders,drug and alcohol addiction, movement disorders, convulsive disorderssuch as epilepsy, migraine, headache, multiple sclerosis and otherdemyelinating diseases, AIDS related neuropathy, chemotherapy-inducedneuropathy and neuralgia, diabetic or peripheral neuropathy, neurogenicinflammation, inflammatory pain, neuropathic pain, and other types ofchronic or acute pain, Reynaud's disease, vasodilation, vasospasm,angina, asthma, chronic obstructive pulmonary diseases, airwayhyperreactivity, cough, allergic rhinitis, bronchospasm,bronchopneumonia, ocular inflammation, inflammatory bowel disease,Crohn's disease, ulcerative colitis, biliary disfunction, skin disordersand itch, hypersensitivity disorders, atopic dermatitis, contactdermatitis, cutaneous wheal and flare, renal disorders, urinaryincontinence, immune system disorders and adverse immunologicalreactions, fibrositis, osteoarthritis, eosinophilic fascioliasis, andscleroderma.

The present invention also pertains to methods of inhibiting the bindingof neurokinin to the NK-3 receptor which methods involve contacting acompound of the invention with cells expressing NK-3 receptors, whereinthe compound is present at a concentration sufficient to inhibitneurokinin binding to cells expressing a cloned human NK-3 receptor invitro. This method includes inhibiting the binding of neurokinin to NK-3receptors in vivo, e.g., in a patient given an amount of a compound ofFormula I that would be sufficient to inhibit the binding of neurokininto NK-3 receptors in vitro. The amount of a compound that would besufficient to inhibit the binding to neurokinin to the NK-3 receptor maybe readily determined via an NK-3 receptor binding assay, such as theassay described in Example 35.

The present invention also pertains to methods for altering thesignal-transducing activity of NK-3 receptors, said method comprisingexposing cells expressing such receptors to an effective amount of acompound of the invention. This method includes altering thesignal-transducing activity of NK-3 receptors in vivo, e.g., in apatient given an amount of a compound of Formula I that would besufficient to alter the signal-transducing activity of NK-3 receptors invitro. The amount of a compound that would be sufficient to alter thesignal-transducing activity of NK-3 receptors may be determined via anNK-3 receptor signal transduction assay, such as the assay described inExample 36.

The NK-3 antagonist compounds provided by this invention and labeledderivatives thereof are also useful as standards and reagents indetermining the ability of a potential pharmaceutical to bind to theNK-3 receptor.

Labeled derivatives the NK-3 antagonist compounds provided by thisinvention are also useful as radiotracers for positron emissiontomography (PET) imaging or for single photon emission computerizedtomography (SPECT).

If the compound of the invention is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be employed to prepare non-toxic pharmaceutically acceptableaddition salts of the compounds encompassed by Formula I.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, diphosphoric, hydrobromic, stearic, sulfuric,sulfinic, formic, fumaric, toluenesulfonic, methanesulfonic, nitric,salicylic, 2-hydroxyethylsulfonic, benzoic, citric, tartaric, lactic,malic, maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)_(n)—ACOOHwhere n is 0–4, and the like. Those skilled in the art will recognize awide variety of non-toxic pharmaceutically acceptable addition salts.Similarly, pharmaceutically acceptable cations include, but are notlimited to sodium, potassium, calcium, aluminum, lithium and ammonium.

The present invention also encompasses the prodrugs of the compounds ofFormula I. Those skilled in the art will recognize various syntheticmethodologies that may be employed to prepare non-toxic pharmaceuticallyacceptable prodrugs of the compounds encompassed by Formula I. See forexample N. Bodor, Drugs of the Future, 1981, 6, 165–182, and H.Bundgaard, Advanced Drug Delivery Reviews, 1989, 3, 39–65.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. Oral administration in theform of a pill, capsule, elixir, syrup, lozenge, troche, or the like isparticularly preferred. The term parenteral as used herein includessubcutaneous injections, intradermal, intravascular (e.g., intravenous),intramuscular, spinal, intrathecal injection or like injection orinfusion techniques. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvantsand if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients that are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories, e.g., for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such, materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. However, for treatment of most disorders, adosage regimen of 4 times daily or less is preferred. For the treatmentof schizophrenia, depression, or obesity a dosage regimen of 1 or 2times daily is particularly preferred.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preferred compounds of the invention have certain pharmacologicalproperties. Such properties include, but are not limited to oralbioavailability, low toxicity, low serum protein binding and desirablein vitro and in vivo half-lifes. Penetration of the blood brain barrierfor compounds used to treat CNS disorders is necessary, while low brainlevels of compounds used to treat periphereal disorders are generallypreferred.

Assays may be used to predict these desirable pharmacologicalproperties. Assays used to predict bioavailability include transportacross human intestinal cell monolayers, including Caco-2 cellmonolayers. Toxicity to cultured hepatocyctes may be used to predictcompound toxicity. Penetration of the blood brain barrier of a compoundin humans may be predicted from the brain levels of the compound inlaboratory animals given the compound intravenously.

Serum protein binding may be predicted from albumin binding assays. Suchassays are described in a review by Oravcová, et al. (Journal ofChromatography B (1996) volume 677, pages 1–27).

Compound half-life is inversely proportional to the frequency of dosageof a compound. In vitro half-lifes of compounds may be predicted fromassays of microsomal half-life as described by Kuhnz and Gieschen (DrugMetabolism and Disposition, (1998) volume 26, pages 1120–1127).

The present invention also pertains to packaged pharmaceuticalcompositions for treating disorders responsive to NK-3 receptormodulation, e.g., treatment of schizoprenia, depression, or chronicpulmonary obstructive disorder by NK-3 receptor modulation. The packagedpharmaceutical compositions include a container holding atherapeutically effective amount of at least one NK-3 receptor modulatoras described supra and instructions (e.g., labeling) indicating thecontained NK-3 receptor ligand is to be used for treating a disorderresponsive to NK-3 receptor modulation in the patient.

Compounds of Formula I wherein X is O are prepared by the methoddescribed in Scheme I.

In Scheme I, R₁, R₂, R₃, Q₁ and Q₂ are as defined above for Formula I,and R₁₁ is methyl, ethyl or benzyl. BOP isbenzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluoro-phosphate.Base is triethylamine, diisoproylethylamine, N-methylmorpholine or othersuitable organic base. DMF is dimethylformide. DMA is dimethylacetamide.Heat as used herein means elevated temperature, such as, for example, 40to 250° C.

Compounds of the invention where X is S or N—CN can be prepared usingsimilar reactions. Alternatively, the compounds of Formula I where X isO can be converted to the corresponding compounds were X is S or N—CN.

Compounds of Formula IV are prepared using literature procedures severalpublications including Jacobs, T. L. et al.; Org. Synth. Coll. 1955,Vol. 3, 456–58 and Lyle R. E. et al. J. Org. Chem. 1972, 37, 3967–68 ifthey are not commercially available. Compounds of Formula V are preparedby a method described in Batt D. G. et al. Bioorg. Med. Chem. Lett.1998, 8, 1745–50. Those skilled in the art will recognize that incertain instances it will be necessary to utilize compounds of FormulaIV bearing protecting groups and that these groups can be removed in asubsequent reaction to yield compounds of Formula I as described in“Protective Groups in Organic Synthesis”, 2nd Ed., Greene, T. W. andrelated publications.

In some situations, the replacement of Y with Q₂ or a protected form ofQ₂ may be facilitated by use of a palladium catalyst as described inBuchwald, S. L. et al in J. Org. Chem. 2000, 65, 1144–57 and 1158–74.Typical conditions for this reaction include but are not limited totreatment of the 2-chloro or 2-bromoquinoline derivative with Q₂H,sodium tert-butoxide, catalytictris(dibenzylideneacetone)-dipalladium(0) and catalytic BINAP([1,1′-bisnaphthalene]-2,2′-diylbis(diphenylphosphine)) in toluene at50–120° C. These reaction conditions are often useful for efficientconversion of Y to Q₂ when R₃ is not hydrogen.

Those having skill in the art will recognize that the startingmaterials, solvents, and other reaction conditions may be varied andadditional steps employed to produce compounds encompassed by thepresent invention. In some cases protection of certain reactivefunctionalities may be necessary to achieve some of the abovetransformations. In general the need for such protecting groups will beapparent to those skilled in the art of organic synthesis as well as theconditions necessary to attach and remove such groups.

The invention is illustrated further by the following examples, whichare not to be construed as limiting the invention in scope or spirit tothe specific procedures described in them.

The disclosures of all articles and references mentioned in thisdocument, including patents, are incorporated herein by reference.

EXAMPLE 1 (S)-N-(α-Ethylphenyl)-2-bromoquinoline-4-carboxamide

A mixture of methyl 2-bromoquinolinecarboxylate (7.2 g) and NaOH (1.1 g)in 15 mL of methanol and 15 mL of water is stirred at 50° C. until TLCindicates the disappearance of starting material. After cooling, themethanol is evaporated and the mixture is treated with 28 mL of 1N HCl,the solid is collected by filtration and dried to afford 6.1 g of2-bromoquinoline-4-carboxylic acid.

To a solution of 2-bromoquinoline-4-carboxylic acid (2.6 g) in 25 mL ofDMF containing is added BOP (5.0 g), followed by (S)-1-phenylpropylamine(2.8 g). The reaction mixture is stirred overnight at room temperature.The mixture is diluted with 20 mL of CH₂Cl₂, then washed with aqueousNaHCO₃, aqueous citric acid and brine. After drying over Na₂SO₄ thesolvent is evaporated to afford the corresponding compound is obtainedas a white solid.

EXAMPLE 2(S)-N-(α-Ethylphenyl)-2-(pyrrolidin-1-yl)-quinoline-4-carboxamide

A solution of (S)-N-(α-Ethylphenyl)-2-bromoquinoline-4-carboxamide (500mg), pyrroline (1 mL) and-triethylamine (1 mL) in 5 mL of DMF in asealed tube is heated with stirring for 8 hours. The reaction mixture ispoured into ice-water. The product is collected by filtration, washedwith water and dried. The corresponding compound is obtained as a tansolid.

The following examples listed in Table 1 are prepared using proceduresanalogous to those set forth above. MS data are given as [MH]⁺. LC-MSdata are given as HPLC retention times and [MH]⁺. The HPLC retentiontimes shown in Table 1 are obtained essentially according to the methoddescribed in Example 1.

TABLE 1

HPLC retention time Example R₃ —Q₂ Compound Name (min) [MH]⁺ 3 H

(S)-N-(α-ethylphenyl)-2-(piperidin-1-yl)-quinoline-4-carboxamide  NA*374 4 H

(S)-N-(α-ethylphenyl)-2-(1,2,5,6-tetrahydropyridin-1-yl)-quinoline-4-carboxamide2.17 372 5 H

(S)-N-(α-ethylphenyl)-2-(N,N-methylbenzylamino)-quinoline-4-carboxamide2.30 410 6 H

(S)-N-(α-ethylphenyl)-2-(homopiperidin-1-yl)-quinoline-4-carboxamide2.23 388 7 H

(S)-N-(α-ethylphenyl)-2-(1,2,3,4-tetrahyroisoquinolin-2-yl)-quinoline-4-carboxamide2.30 422 8 H

(S)-N-(α-ethylphenyl)-2-(morpholin-4-yl)-quinoline-4-carboxamide 2.09376 9 H

(S)-N-(α-ethylphenyl)-2-(thiomorpholin-4-yl)-quinoline-4-carboxamide2.17 392 10 H

(S)-N-(α-ethylphenyl)-2-(4-methylpiperidine-1-yl)-quinoline-4-carboxamide2.26 389 11 H

(S)-N-(α-ethylphenyl)-2-(3,3-dimethylpiperidin-1-yl)-quinoline-4-carboxamide2.31 402 12 H

(S)-N-(α-ethylphenyl)-2-(aza-1,4-dioxaspiro[4.5]decanyl-8-yl)-quinoline-4-carboxamide2.17 432 13 H

(S)-N-(α-ethylphenyl)-2-(N-methyl-N-n-butylamino)-quinoline-4-carboxamide2.27 376 14 H

(S)-N-(α-Ethylphenyl)-2-(3,,5,5-trimethylhomopiperidn-1-yl)-quinoline-4-carboxamide2.47 430 15 H

(S)-N-(α-Ethylphenyl)-2-(2-methylpiperidn-1-yl)-quinoline-4-carboxamide2.22 388 16 H

(S)-N-(α-ethylphenyl)-2-(2-ethylpiperidn-1-yl)-quinoline-4-carboxamide2.27 402 17 H

(S)-N-(α-ethylphenyl)-2-(N-methyl-N-cyclohexylamino)-quinoline-4-carboxamide2.27 402 18 H

(S)-N-(α-ethylphenyl)-2-(N-n-propyl-N-cyclopropylmethylamino)-quinoline-4-carboxamide2.29 402 19 H

(S)-N-(α-ethylphenyl)-2-(N-ethyl-N-n-butylamino)-quinoline-4-carboxamide2.30 390 20 H

(S)-N-(α-ethylphenyl)-2-(4-methylpiperazin-1-yl)-quinoline-4-carboxamide2.09 389 21 H

(S)-N-(α-ethylphenyl)-2-(3-hydroxypyrrolidin-1-yl)-quinoline-4-carboxamide2.07 376 22 H

(S)-N-(α-ethylphenyl)-2-[(S)-2-methoxymethyl-pyrrolidin-1-yl]-quinoline-4-carboxamide2.18 404 23 H

(S)-N-(α-ethylphenyl)-2-[(S)-2-hydroxymethylpyrrolidin-1-yl]-quinoline-4-carboxamide2.09 390 24 H

(S)-N-(α-ethylphenyl)-2-(2-carboxypyrrolidin-1-yl)-quinoline-4-carboxamide2.12 404 25 H

(S)-N-(α-ethylphenyl)-2-(3-hydroxymethypiperidin-1-yl)-quinoline-4-carboxamide2.13 404 26 H

(S)-N-(α-ethylphenyl)-2-(2-hydroxymethypiperidin-1-yl)-quinoline-4-carboxamideNA 404 27 H

(S)-N-(α-ethylphenyl)-2-(3-hydroxypiperidin-1-yl)-quinoline-4-carboxamide2.09 390 28 H

(S)-N-(α-ethylphenyl-2-[2-(1-hydroxyethy)piperidin-1-yl]-quinoline-4-carboxamideNA 418 29 H

(S)-N-(α-Ethylphenyl)-2-(N-α-methylbenzylamino)-quinoline-4-carboxamideNA 410 30 H

(S)-N-(α-Ethylphenyl)-2-(azabicyclo[3.2.2]nonan-3-yl)-quinoline-4-carboxamide.2.30 414 31 CH₃

(S)-N-(α-Ethylphenyl)-3-methyl-2-(pyrrolidin-1-yl)-quinoline-4-carboxamideNA 374 32 CH₃

(S)-N-(α-Ethylphenyl)-3-methyl-2-(piperidin-1-yl)-quinoline-4-carboxamideNA 388 33 OCH₃

(S)-N-(α-Ethylphenyl)-3-methoxy-2-(pyrrolidin-1-yl)-quinoline-4-carboxamideNA NA 34 OCH₃

(S)-N-(α-Ethylphenyl)-3-methoxy-2-(piperidin-1-yl)-quinoline-4-carboxamideNA NANA: not determined

The compound of Example 33 can be prepared according to the followingprocedure.

A solution of(S)-N-(α-Ethylphenyl)-2-bromo-3-methoxyquinoline-4-carboxamide (500 mg),pyrroline (106 mg), sodium tert-butoxide (1.75 mmol), Pd₂(dba)₃ (0.003mmol) and BINAP (0.0094 mmol) in toluene (2.5 ml) under argon isimmersed in an oil bath at 80° C. with magnetic stirring. After completeconsumption of starting bromide, the reaction mixture is allowed to coolto ambient temperature, diluted with ethyl acetate (10 ml), filtered,concentrated and purified by chromatography on silica gel to yield thedesired product.

The compound of Example 34 can be prepared according to the followingprocedure.

A solution of(S)-N-(α-Ethylphenyl)-2-bromo-3-methoxyquinoline-4-carboxamide (500 mg),piperidine (128 mg), sodium tert-butoxide (1.75 mmol), Pd₂(dba)₃ (0.003mmol) and BINAP (0.0094 mmol) in toluene (2.5 ml) under argon isimmersed in an oil bath at 80° C. with magnetic stirring. After completeconsumption of starting bromide, the reaction mixture is allowed to coolto ambient temperature, diluted with ethyl acetate (10 ml), filtered,concentrated and purified by chromatography on silica gel to yield thedesired product.

EXAMPLE 35 NK-3 Receptor Binding Assay

The following assay is a standard assay of NK3 receptor binding, whichis used to determine the NK-3 receptor binding affinity of compounds.

Assays are performed as described in Krause et al (Proc. Natl. Acad.Sci. USA 94: 310–315, 1997). The NK-3 receptor complementary DNA wascloned from human hypothalamic RNA using standard procedures. Thereceptor cDNA was inserted into the expression vector pM² to transfectthe mammalian Chinese hamster ovary cell line, and a stably expressingclonal cell line was isolated, characterized and used for the currentexperiments. Cells are grown in minimal essential medium alphacontaining 10% fetal bovine serum and 0.8 mg G418 per ml. Cells wereliberated from cell culture plates with No-zyme (PBS base, JRHBiosciences), and harvested by low speed centrifugation. The cell pelletwas homogenized in TBS (0.05 m TrisHCl, 120 mM NaCl, pH 7.4) with aPolytron homogenizer at setting 5 for 20 seconds, and total cellularmembranes were isolated by centrifugation at 47,500×g for 10 minutes.The membrane pellet was resuspended by homogenization with the Polytronas above, and the membranes were isolated by centrifugation at 47,500×gfor 10 minutes. This final membrane pellet was resuspended in TBS at aprotein concentration of 350 μg/ml.

Receptor binding assays contain a total volume of 200 μl containing 50μg membrane protein, 0.15 nM ¹²⁵I-methylPhe⁷-neurokinin B, drug orblocker in TBS containing 1.0 mg/ml bovine serum albumen, 0.2 mg/mlbacitracin, 20 μg/ml leupeptin and 20 μg/ml chymostatin. Incubations arecarried out for 2 hours at 4°, and the membrane proteins are harvestedby passing the incubation mixture by rapid filtration over presoakedGF/B filters to separate bound from free ligand. The filters arepresoaked in TBS containing 2% BSA and 0.1% Tween 20. After filtrationof the incubation mixture, filters are rinsed 4 times with ice-cold TBScontaining 0.01% sodium dodecyl sulfate and counted in a β-platescintillation counter. One μM methylPhe⁷-neurokinin B is added to sometubes to determine nonspecific binding. Data are collected in duplicatedeterminations, averaged, and the percent inhibition of total specificbinding is calculated. The total specific binding is the total bindingminus the nonspecific binding. In many cases, the concentration ofunlabeled drug is varied and total displacement curves of binding arecarried out. Data are converted to a form for the calculation of IC₅₀and Hill coefficient (nH). Compounds of Formula I display IC₅₀ valuesless than 5 μM. Preferred compounds of Formula I display IC₅₀ values ofless than 1 μM, more preferred compounds of Formula I display IC₅₀values of less than 1 μM, still more preferred compounds of Formula Idisplay IC₅₀ values of less than 100 nM, and particularly preferredcompounds of Formula I display IC₅₀ values of less than 10 nM.

EXAMPLE 36 Assay for NK-3 Functional Activity

Calcium Mobilization Assays:

The human NK-3 bearing Chinese hamster ovary cells are grown in minimalessential media supplemented with 250 ug/ml G418, 10% fetal bovine serumand 25 mM Hepes, pH=7.4. Forty eight hours prior to the day of assay,the cells are plated in fresh media that does not contain the G418. Onthe day of assay, cells grown to 70–90% confluency in 96-well plates arewashed with Krebs-Ringer buffer (25 mM HEPES, 5 mM KCl, 0.96 mM NaH₂PO₄,1 mM MgSO₄, 2 mM CaCl₂, 5 mM glucose, 1 mM probenecid, pH 7.4) and arethen incubated for 1–2 hours in the above buffer supplemented withFluo3-AM (2.5 to 10 μg/ml; Teflabs) at 37 degrees C. in an environmentcontaining 5% CO₂. The wells are then washed twice with Krebs RingersHEPES buffer. Agonist-induced (methylPhe7-neurokinin B) calciummobilization is monitored using a FLIPR (Molecular Devices) instrument.The agonist is added to the cells and fluorescence responses arecontinuously recorded for up to 5 min. For the examination of antagonistdrug candidates, compounds are preincubated with the cells for up to 30min. prior to administration of the methylPhe7-neurokinin B agonistusually at a concentration that brings about a 50% maximal activity.Responses are recorded for times up to 5 min. Kaleidagraph software(Synergy Software, Reading, Pa.) is utilized to fit the data to theequation y=a*(1/(1+(b/x)c)) to determine the EC₅₀ value or IC₅₀ valuefor the response. In this equation, y is the maximum fluorescencesignal, x is the concentration of the agonist or antagonist, a is theE_(max), b corresponds to the EC₅₀ or IC₅₀ value, and, finally, c is theHill coefficient.

EXAMPLE 37 Preparation of Radiolabeled Probe Compounds of the Invention

The compounds of the invention are prepared as radiolabeled probes bycarrying out their synthesis using precursors comprising at least oneatom that is a radioisotope. The radioisotope is preferably selectedfrom of at least one of carbon (preferably ¹⁴C), hydrogen (preferably³H), sulfur (preferably ³⁵S), or iodine (preferably ¹²⁵I). A commerciallaboratory specializing in custom synthesis of radiolabeled probecompounds conveniently carries out synthesis of such radiolabeledprobes. Such laboratories include Amersham Corporation, ArlingtonHeights, Ill.; Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRIInternational, Menlo Park, Calif.; Wizard Laboratories, West Sacramento,Calif.; ChemSyn Laboratories, Lexena, Kans.; American RadiolabeledChemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea,Calif.

Tritium-labeled probe compounds are also conveniently preparedcatalytically via platinum-catalyzed exchange in tritiated acetic acid,acid-catalyzed exchange in tritiated trifluoroacetic acid, orheterogeneous-catalyzed exchange with tritium gas. Such preparations arealso conveniently carried out as a custom radiolabeling by any of thesuppliers listed in the preceding paragraph using the compound of theinvention as substrate. In addition, certain precursors may be subjectedto tritium-halogen exchange with tritium gas, tritium gas reduction ofunsaturated bonds, or reduction using sodium borotritide, asappropriate.

EXAMPLE 38 Use of Compounds of the Invention as Probes for DetectingNK-3 Receptors in Cultured Cells and Tissue Samples (e.g., TissueSections)

Receptor autoradiography (receptor mapping) of NK-3 receptors incultured cells or tissue samples is carried out in vitro as described byKuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology(1998) John Wiley & Sons, New York, using radiolabeled compounds of theinvention prepared as described in the preceding Example.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

1. A packaged pharmaceutical composition comprising a compound of theformula:

or a pharmaceutically acceptable salt or pharmaceutically acceptablesolvate thereof, in a container and instructions for using thecomposition to treat a patient suffering from anxiety, depression,schizophrenia, obesity, chronic pulmonary obstructive disorder, or painwherein: R₁ is selected from: hydrogen, halogen, hydroxy, C₁₋₆alkyl,—O(C₁₋₆alkyl), —NO₂, —CN, —SO₂NH₂, —SO₂NH(C₁₋₆alkyl),—SO₂N(C₁₋₆alkyl)(C₁₋₆alkyl), amino, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)(C₁₋₆alkyl), —N(C₁₋₆alkyl)CO(C₁₋₆alkyl), —NHCO₂(C₁₋₆alkyl),—N(C₁₋₆alkyl)CO₂(C₁₋₆alkyl), —NHSO₂(C₁₋₆alkyl),—N(C₁₋₆alkyl)SO₂(C₁₋₆alkyl), —SO₂NHCO(C₁₋₆alkyl), —CONHSO₂(C₁₋₆alkyl),—CON(C₁₋₆alkyl)(C₁₋₆alkyl), —CO₂(C₁₋₆alkyl), —S(C₁₆alkyl),—SO(C₁₋₆alkyl), or —SO₂(C₁₋₆alkyl), wherein said C₁₋₆alkyl may bestraight, branched or cyclic, may contain one or two double or triplebonds, unsubstituted or substituted with one or more substituentsselected from: hydroxy, oxo, halogen, amino, and C₁₋₃ alkoxy; R₂ and R₃are independently selected from the group consisting of: hydrogen,halogen, hydroxy, C₁₋₈alkyl, —O(C₁₋₈alkyl), —NO₂, —CN, —SO₂NH₂,—SO₂NH(C₁₋₈alkyl), —SO₂N(C₁₋₈alkyl)(C₁₋₈alkyl), amino, —NH(C₁₋₈alkyl),—N(C₁₋₈alkyl)(C₁₋₈alkyl), —N(C₁₋₈alkyl)CO(C₁₋₈alkyl), —NHCO₂(C₁₋₆alkyl),—N(C₁₋₈alkyl)CO₂(C₁₋₈alkyl), —NHSO₂(C₁₋₈alkyl),—N(C₁₋₆alkyl)SO₂(C₁₋₈alkyl), —SO₂NHCO (C₁₋₈alkyl), —CONHSO₂(C₁₋₈alkyl),—CON (C₁₋₈alkyl)(C₁₋₈alkyl), —CO₂(C₁₋₈alkyl), —S(C₁₋₈alkyl),—SO(C₁₋₈alkyl), —SO₂(C₁₋₈alkyl), and Ar, wherein Ar is phenyl, naphthyl,thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl,imidazolyl, benzoimidazolyl, furanyl, benzofuranyl, thiazolyl,benzothiazolyl, isothiazolyl, benzoisothiazolyl, triazolyl, tetrazolyl,pyrazolyl, or benzopyrazolyl, each of which is unsubstituted orsubstituted with one or more substituents selected from: halogen,hydroxy, C₁₋₆alkyl, —O(C₁₋₆alkyl), —NO₂, —CN, —SO₂NH₂,—SO₂NH(C₁₋₆alkyl), —SO₂N(C₁₋₆alkyl)(C₁₋₆alkyl), amino, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)(C₁₋₆alkyl), —N(C₁₋₆alkyl)CO(C₁₋₆alkyl), —NHCO₂(C₁₋₆alkyl),—N(C₁₋₆alkyl)CO₂(C₁₋₆alkyl), —NHSO₂(C₁₋₆alkyl),—N(C₁₋₆alkyl)SO₂(C₁₋₆alkyl), —SO₂NHCO(C₁₋₆alkyl), —CONHSO₂(C₁₋₆alkyl),—CON(C₁₋₆alkyl)(C₁₋₆alkyl), —CO₂(C₁₋₆alkyl), —S(C₁₋₆alkyl),—SO(C₁₋₆alkyl), or —SO₂(C₁₋₆alkyl), wherein C₁₋₆alkyl, is defined asabove, wherein said C₁₋₈alkyl and said C₁₋₆alkyl may be straight,branched or cyclic, may contain one or two double or triple bonds,unsubstituted or substituted with one or more substituents selectedfrom: (i) hydroxy, (ii) oxo, (iii) halogen, (iv) Ar, wherein Ar is asdefined above, (v) —NR₄R₅, wherein R₄ and R₅ are independently selectedfrom: (A) hydrogen, (B) C₁₋₆alkyl, wherein C₁₋₆alkyl is as definedabove, (C) Ar, wherein Ar is as defined above, (D) C₁₋₆alkyl-Ar, whereinAr is as defined above and Ar is attached to any position of theC₁₋₆alkyl at any position of Ar, and the groups R₄ and R₅ may be joinedtogether to form a 4- to 8-membered monocyclic or bicyclic ring whichmay contain: (a) one or two double bonds, (b) one or two oxo, (c) one ortwo O, S or N—R₆ wherein R₆ is hydrogen, C₁₋₆alkyl, C₁₋₆alkyl-Ar,wherein C₁₋₆alkyl and Ar are defined as above and Ar is attached toC₁₋₆alkyl at any position, (d) one or two R₁, (vi) —OR₄, wherein R₄ isas defined above, (vii) —CONR₄R₅, wherein R₄ and R₅ are as definedabove, (viii) —SO₂NR₄R₅, wherein R₄ and R₅ are as defined above, (ix)—NR₄COR₅, wherein R₄ and R₅ are as defined above; X is O or S; Q₁ isselected from Formulas A and B:

wherein R₁₇ is hydrogen or C₁₋₈alkyl, wherein C₁₋₈alkyl carries thedefinition assigned above, Ar₁₈ is phenyl, naphthyl, thienyl,benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl,benzoimidazolyl, furanyl, benzofuranyl, thiazolyl, benzothiazolyl,isothiazolyl, benzoisothiazolyl, triazolyl, tetrazolyl, pyrazolyl, orbenzopyrazolyl, each of which is unsubstituted or substituted with oneor more substituents selected from: halogen, hydroxy, C₁₋₈alkyl,—O(C₁₋₈alkyl), —NO₂, —CN, —SO₂NH₂, —SO₂NH(C₁₋₈alkyl),—SO₂N(C₁₋₈alkyl)(C₁₋₈alkyl), amino, —NH(C₁₋₈alkyl),—N(C₁₋₈alkyl)(C₁₋₈alkyl), —N(C₁₋₈alkyl)CO(C₁₋₈alkyl), —NHCO₂(C₁₋₆alkyl),—N(C₁₋₈alkyl)CO₂(C₁₋₈alkyl), —NHSO₂(C₁₋₈alkyl),—N(C₁₋₆alkyl)SO₂(C₁₋₈alkyl), —SO₂NHCO(C₁₋₈alkyl), —CONHSO₂(C₁₋₈alkyl),—CON(C₁₋₈alkyl)(C₁₋₈alkyl), —CO₂(C₁₋₈alkyl), —S(C₁₋₈alkyl),—SO(C₁₋₈alkyl), —SO₂(C₁₋₈alkyl), wherein C₁₋₈alkyl, is defined as above,and R₁₈ are R₁₉ are independently (i) hydrogen, (ii) Ar₁₉ wherein Ar₁₉carries the definition of Ar₁₈, (iii) C₁₋₈alkyl, wherein said C₁₋₈alkylis as defined above, (iv) —COR₄, wherein R₄ is as defined above; (v)—CONR₄R₅, wherein R₄ and R₅ are as defined above, (vi) —SO₂NR₄R₅,wherein R₄ and R₅ are as defined above; and Q₂ is selected from FormulasII and III:

wherein R₇ is hydrogen or C₁₋₈ alkyl, wherein C₁₋₈ alkyl as definedabove, wherein R₈ and R₉ are independently selected from: (i) hydrogen,(ii) Ar′, wherein Ar′ is phenyl, naphthyl, thienyl, benzothienyl,pyridyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, benzoimidazolyl,furanyl, benzofuranyl, thiazolyl, benzothiazolyl, isothiazolyl,benzisothiazolyl, triazolyl, tetrazolyl, pyrazolyl, or benzopyrazolyl,each of which is unsubstituted or substituted with one or moresubstituents selected from: halogen, hydroxy, C₁₋₈ alkyl, —O(C₁₋₈alkyl), —NO₂, —CN, —SO₂NH₂, —SO₂NH(C₁₋₈ alkyl), —SO₂N(C₁₋₈ alkyl)(C₁₋₈alkyl), amino, —NH(C₁₋₈ alkyl), —N(C₁₋₈ alkyl)(C₁₋₈ alkyl), —N(C₁₋₈alkyl)CO(C₁₋₈ alkyl), —NHCO₂(C₁₋₆ alkyl), —N(C₁₋₈ alkyl)CO₂(C₁₋₈ alkyl),—NHSO₂(C₁₋₈ alkyl), —N(C₁₋₆ alkyl)SO₂(C₁₋₈ alkyl), —SO₂NHCO(C₁₋₈ alkyl),—CONHSO₂(C₁₋₈ alkyl), —CON(C₁₋₈ alkyl)(C₁₋₈ alkyl), —CO₂(C₁₋₈ alkyl),—S(C₁₋₈ alkyl), —SO(C₁₋₈ alkyl), —SO₂(C₁₋₈ alkyl), wherein C₁₋₈ alkyl,is defined as above, (iii) C₁₋₈ alkyl, wherein said C₁₋₈ alkyl is asdefined above, (iv) —COR₄, wherein R₄ is as defined above, (v) —CONR₄R₅,wherein R₄ and R₅ are as defined above, (vi) —SO₂NR₄R₅, wherein R₄ andR₅ are as defined above or the groups R₈ and R₉, may be joined togetherto form a 4- to 8-membered monocyclic or bicyclic ring of which maycontain: (a) one or two double bonds, (b) one or two oxo, (c) one or twoO, S or N—R₁₀ wherein R₁₀ is hydrogen, C₁₋₈ alkyl, C₁₋₈ alkyl-Ar′,wherein C₁₋₈ alkyl and Ar′ are defined as above and Ar′ is attached toany position of the C₁₋₈ alkyl group at any position or Ar′, (d) one ortwo R₁.
 2. A packaged pharmaceutical composition according to claim 1,where the compound has the formula:

where R_(q) is straight or branched chain alkyl having from 1–6 carbonatoms.
 3. A packaged pharmaceutical composition according to claim 2wherein: R_(q) is ethyl; and R₈ and R₉ are independently selected from:hydrogen; C₁₋₈ alkyl, wherein said C₁₋₈ alkyl is as defined above; or R₈and R₉ together form a 4- to 8-membered monocyclic or bicyclic ringwhich may contain: (a) one or two double bonds; (b) one or two oxo; (c)one or two O, S or N—R₁₀ wherein R₁₀ is hydrogen, C₁₋₈ alkyl, C₁₋₈alkyl-Ar′, wherein C₁₋₈ alkyl and Ar′ are defined as above and Ar′ maybe attached to C₁₋₈ alkyl at any position; or (d) one or two R₁ groups.4. A packaged pharmaceutical composition according to claim 1, where thecompound has the formula:

wherein: R_(q) is straight or branched chain alkyl having from 1–6carbon atoms; and R₃ is C₁₋₆ alkyl or C₁₋₆ alkoxy.
 5. A packagedpharmaceutical composition according to claim 4 wherein: R_(q) is ethyl;and Q₂ is a group of the formula:

wherein R₈ and R₉ together form a 4- to 8-membered monocyclic orbicyclic ring which may contain: (a) one or two double bonds; (b) one ortwo oxo; (c) one or two O, S or N—R₁₀ wherein R₁₀ is hydrogen, or C₁₋₈alkyl.
 6. A packaged pharmaceutical composition according to claim 1,wherein the compound is:(S)-N-(1-phenylpropyl)-2-(pyrrolidin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(piperidin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(1,2,5,6-tetrahydropyridin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(N,N-methylbenzylamino)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(homopiperidn-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(morpholin-4-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(thiomorpholin-4-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(4-methylpiperidin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(3,3-dimethylpiperidin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(aza-1,4-dioxaspiro[4.5]decanyl-8-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(N-methyl-N-n-butylamino)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(3,5,5-trimethylhomopiperidn-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(2-methylpiperidn-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(2-ethylpiperidn-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(N-methyl-N-cyclohexylamino)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(N-n-propyl-N-cyclopropylmethylamino)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(N-ethyl-N-n-butylamino)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(4-methylpiperazin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(3-hydroxypyrrolidin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-[(S)-2-methoxymethylpyrrolidin-1-yl]-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-[(S)-2-hydroxymethylpyrrolidin-1-yl]-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(2-carboxypyrrolidin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(3-hydroxymethypiperidin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(2-hydroxymethypiperidin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(3-hydroxypiperidin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-[2-(2-hydroxyethyl)piperidin-1-yl]-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(N-α-methylbenzylamino)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-2-(azabicyclo[3.2.2]nonan-3-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-3-methyl-2-(pyrrolidin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-3-methyl-2-(piperidin-1-yl)-quinoline-4-carboxamide;(S)-N-(1-phenylpropyl)-3-methoxy-2-(pyrrolidin-1-yl)-quinoline-4-carboxamide;or(S)-N-(1-phenylpropyl)-3-methoxy-2-(piperidin-1-yl)-quinoline-4-carboxamide.7. The packaged pharmaceutical composition of claim 1, wherein saidpatient is suffering from anxiety.
 8. The packaged pharmaceuticalcomposition of claim 1, wherein said patient is suffering fromschizophrenia.
 9. The packaged pharmaceutical composition of claim 1,wherein said patient is suffering from chronic pulmonary obstructivedisorder.
 10. The packaged pharmaceutical composition of claim 1,wherein said patient is suffering from pain.
 11. The packagedpharmaceutical composition of claim 1, wherein said patient is sufferingfrom depression.